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This article was sent to me from The Director of Pre Clinical Trials ..Very Interesting
Finding a Cure for Retinal Degenerative DiseasesThe Promise of Stem Cell Therapies I. Executive SummaryThe Foundation Fighting Blindness (FFB) proposes to expand its existingconsortium of the world’s leading researchers in stem cell therapies to accelerateadvances in finding treatments and cures for retinal degenerative diseases.Stem cell therapies hold great promise for restoring vision to individuals whohave lost their sight, or are rapidly losing their sight, due to death ofphotoreceptor cells—rods and cones—located in the retina. A stem cell is a cell whose job in the body hasn’t yet been determined. Every cellin the body “stems” from this type of cell. There are many types of stem cells thathave different names based upon how specialized the cells have become. Goingfrom the least specialized to the most specialized, these are: embryonic,progenitor/precursor, umbilical, and adult stem cells. As a stem cell becomesmore specialized, there are fewer cells that it can ultimately become. Forinstance, retinal adult stem cells can only become cells in the retina, not cells ofthe skin or other body part. However, no matter what stem cell is used as thestarting material, the goal of any stem cell therapy is to repair a damaged tissuethat can't heal itself. As the science and efficacy of stem cell replacement therapy advances, it holdsgreat promise to individuals who are losing their sight due to retinitis pigmentosa,advanced macular degeneration, Leber congenital amaurosis, and other retinaldiseases that result in photoreceptor cell death. Photoreceptor cells are those cells which turn light into electrical impulsestransmitted to the brain, where “seeing” actually occurs. When thesephotoreceptor cells die prematurely, the only way to restore their function is toreplace them with “new” cells through transplantation or injection in the eye.In recent years, Foundation-funded researchers from all over the country havemade enormous strides in advancing stem cell therapies to treat the entirespectrum of retinal degenerative diseases. For the first time, scientists havegenerated functional photoreceptors from developing progenitor/precursor stemcells (stem cells that already have begun to follow a specific path but aren’t attheir final identity), and at the same time, facilitated their integration into the hostretina. These advances bring us much closer to the reality of human clinical trialsof stem cell therapies to save and restore vision. The anticipated five year budget for this program is $11.5 million. II. Research Goals -- Human Phase I Clinical TrialFFB will build on the results of studies it has supported to accelerate the use ofembryonic stem cell transplantation to replace diseased retinal tissue, such asphotoreceptor cells (rods and cones) and retinal pigment epithelial (RPE) cells, tosave and restore vision. Research will use existing and new rodent models and,importantly, non-human primates (e.g., monkeys) as a “proof of principal” tosupport filing an Investigational New Drug Application (IND) with the FDA for ahuman phase I clinical trial within five years. Specifically, the primary anticipated outcome of the FFB research program will beto rapidly accelerate the progress of emerging stem cell therapies to clinical trials. We expect that stem cell therapies will:(1) Arrest photoreceptor and retinal pigment epithelial cell degeneration, theprimary cause of vision loss from retinitis pigmentosa and maculardegeneration; and, (2) Reverse the degeneration by replacing the diseased photoreceptors andretinal pigment epithelial cells with cells manufactured using adult,umbilical cord blood, progenitor/precursor, or embryonic stem cells as thestarting material. The research program will define and optimize the cell production, delivery, andtransplant procedures. This is necessary to enable human clinical trials to beconducted in the safest and most effective manner, thereby optimizing everyopportunity for success. Rationale: Retinitis pigmentosa afflicts between 100,000 and 200,000 peopleannually in the U.S. alone, and several million around the world. More than ninemillion people in the U.S. have many types of degenerative retinal diseases,including Stargardt and Usher diseases that primarily affect children. Age-relatedmacular degeneration (AMD) is a leading cause of blindness in the U.S. and thedeveloped world. The National Eye Institute, a part of the U.S. National Institutesof Health, estimates that 1.7 million Americans have vision loss from advancedAMD, and another 7.3 million face the risk of vision loss from AMD. Given theaging of the baby boomer generation, the government estimates that by 2020,the number of Americans with vision loss from advanced AMD will increase by50% to approximately 3 million. The Foundation Fighting Blindness, the world’s largest source of nongovernmentgrants for retinal disease research, has supported pioneeringinvestigations that have yielded important new insights into causes, preventions,and treatments for retinitis pigmentosa and other retinal diseases. One example of the impact of the Foundation’s support is found in a 2006publication by an FFB-supported researcher which states that transplanation ofdeveloping photoreceptor cells (i.e., developing precursor/progenitor stem cells)into mice with RP led to some evidence of vision restoration. The researchfindings were reported in Nature magazine and were the focus of major newsstories in The Washington Post and The Boston Globe. The FFB is now poised to leverage its previous support to move this landmarkresearch to its next stage — a platform for developing clinical trials. The FFB proposes to invest $11.5 million over five years to support this importantresearch project. If U.S. government support for this project is obtained, researchsupported with these funds would adhere to U.S. governmental regulations forstem cell research. Success of this project will move stem cell therapies closer tothe promise of new therapies to treat the entire spectrum of retinal degenerativediseases. III. Research Overview Goal 1: Develop cells to sustain existing photoreceptors and visualcapability:(A) This phase of the research will explore several stem cell types, includingbut not limited to: i) federally “approved” human embryonic stem cells, onetype of which has already been shown to become photoreceptor cellswhen transplanted into diseased retinas in rodents; ii) new, “nonapproved”human embryonic stem cells; iii) all other stem cells, includingspecialized retinal or brain progenitor stem cells, and umbilical or adultstem cells; and, iv) modified human stem cells (“approved” and “nonapproved”)that secrete specific neuroprotective proteins that preservephotoreceptors and RPE cells. (B) Once the safety and efficacy of the cells are proven, selected cells will beprepared for further development at a facility that meets FDA GoodManufacturing Practices (GMP) and additional safety studies will beconducted. In March 2007, PLoS ONE reported that human neural progenitor cells (hNPCs)were used as effective retina rescue agents. Researchers used two types ofhNPCs: one type is naturally occurring, while the second type is engineered tocontain an additional, non-neural growth factor. Both cell types migrated toappropriate and advantageous locations within the retina, and produced noevidence of unwanted effects. Two members of this research group are part ofthe FFB Stem Cell Consortium. Goal 2: Develop strategies to repopulate the photoreceptor cells andRPE: Stem cells for replacing the diseased cells will be derived primarily fromhuman embryonic stem cells. Only cells that have demonstrated thecapability to produce cell types with retina-specific markers (i.e.,photoreceptor precursor cells) will be used for further testing and gene andprotein analysis. Therefore, a series of cell-surface markers will becharacterized to enable identification and development of these cells from themixed stem cell populations. A set of animal models suitable for sustaining and repopulating photoreceptorcells will be assembled to cover a wide range of retinal degenerative diseases.FFB provided funding for a landmark research project, published in theNovember 9, 2006 issue of Nature, to investigate using transplanted stem cells torestore vision in laboratory mice with retinitis pigmentosa. The study has shownthat transplanted cells could become functioning retinal cells and integrate intothe host retina. In addition, the March 1, 2007 issue of Stem Cells reported that human umbilicalcord tissue cells were used to rescue vision in a specific rodent model of retinaldegenerative disease, a fact that may help treat patients with retinitis pigmentosa. This work was done by an FFB-funded researcher, in collaboration with Centocor, a biomedical company. Goal 3: Define the most appropriate stem cell delivery method usingnon-human primates to support a FDA Investigational New Drugapplication (IND) for a human clinical trial: These studies will define andoptimize the cell delivery procedures [subretinal injection, transplantation on amatrix substrate (a growth “skeleton”), etc.], appropriate dosage, and safety innon-human primates. Subretinal cell injections will be given to healthyprimates, and the outcomes will be studied and evaluated. This phase willinclude generating the development of an acquired outer retinopathy inprimates, designed to test the efficacy of the above-mentioned photoreceptorreplacement techniques. Goal 4: Final preclinical safety studies using GMP manufactured stemcells: This will involve a series of safety studies in addition to those detailedabove, including examining the potential for developing tumors, andcontaining immune reactions, as well as preparing the best cell lines for GMPproduction. IV. Elements Critical to the Success of This Program• The entire research effort has been built around the collective expertise ofan FFB-supported group of investigators, each of whom has acommitment in this area of research and a proven track record of success.• The project will be developed with a rigorous timeline and set ofdeliverables that will be actively monitored.• The project will be conducted with close ties to clinical programs whichcan share findings and knowledge, ensuring the preclinical studiesprogress naturally toward human clinical trials.• Multiple rigorous and clinically relevant safety and efficacy studies will beused to validate each potential stem cell treatment.FFB is actively pursuing relationships with industry for translating the outcomesto clinical trials, and establishing safety and GMP capability. FFB is also meetingwith multiple companies committed to stem cell therapy for retinal degenerativediseases. V. Timelines Years 1-2: Newly-identified and presently-existing stem cells will be usedto test the efficacy of either encouraging the survival of existingphotoreceptors or replacing them in mouse models of specific retinaldegenerations and related diseases. This phase might be extendedbeyond the two year period, based on results, to explore whether theinfusion of additional “helper” cells, or the inclusion of a growth “skeleton”to organize the infused cells, will improve efficacy. Years 2-5: Take “best” cells to GMP level of production. Years 3-5: Compare relative efficacy of cells in appropriate rodent modelsof retinal degenerative diseases and nonhuman primates. Year 5: Prepare and submit regulatory documents for human Phase Iclinical trial. VI. Budget The total five-year cost of this program is estimated to be $11.5million. Ideally, the Foundation would need $4 million incommitments to undertake the project, and would then need to meettarget goals of raising an additional $2.5 million per year in each ofthe next three years to meet the goal and timeline. Fundraising costsare estimated to be $500,000. Cost summary of the program:• Manufacture appropriate cells: $4 million• Test efficacy: $3 million• Examine the feasibility of implanting manufactured cells inprimates: $1 million• Explore issues of safety and GMP production: $2 million• Cost of Fundraising: $500,000 (4.5%)TOTAL: $11.5 million Project leader: Dr. Stephen Rose, Chief Research Officer, Foundation FightingBlindness The Foundation Fighting Blindness: A Proven Leader in Retinal ResearchThe Foundation Fighting Blindness has raised more money for retinaldegenerative disease research than any non-governmental in the United States.Since our inception in 1971, we have raised more than $260 million. TheFoundation funds the world’s top scientific and clinical research experts athundreds of prominent institutions. In the current fiscal year, the Foundation is funding 110 total research grants to115 investigators who are located at 48 institutions around the world. To promotecollaborations between basic and clinical researchers and accelerate treatmentsto the clinic, the Foundation funds 16 collaborative national and internationalresearch centers. These include the Southwest Regional Center for the Study ofRetinal Degenerative Diseases (Retina Foundation of the Southwest, Universityof Texas, and University of Oklahoma) and the Wilmer Eye Institute ResearchCenter for the Study of Retinal Degenerative Diseases (Johns HopkinsUniversity). In 2003, the Foundation established the National Neurovision Research Instituteto accelerate the translation of promising research into clinical trials, and makemore treatments (including stem cell therapies) commercially available to thepeople who need them. As a result, in 2004, the Foundation established the FFB Stem Cell Consortium—a nationwide collaboration of stem cell experts—to quickly advance emergingstem cell treatments for retinal degenerative diseases. Over the past year alone,Consortium scientists have been recognized internationally for making numerous, extraordinary advancements in stem cell research for retinal diseases.
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